The present invention is a novel compound which is a thiadiazole or oxadiazole analog of a fenamic acid having a substituted hydroxamate side chain and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use thereof The invention compounds are now found to have activity as inhibitors of one or both of cyclooxygenase and 5 lipoxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and the like. Thus, the present invention is also a pharmaceutical composition or method of use thereof.
Fenamic acids and hydroxamic acid derivatives of fenamic acids are known antiinflammatory agents, 5-lipoxygenase inhibitors, or cyclooxygenase inhibitors. A few of these references disclosing hydroxamate derivatives of fenamic acids are as follows:
U.S. Pat. No. 4,092,430 disclosing acetohydroxamic acid derivatives of fenamates;
WO 8903818A disclosing N hydroxy(or alkoxy)-N-substituted derivatives and various quinazolinone, indole oxime derivatives or hydroxy imino derivatives of fenamates;
U.S. Pat. No. 5,017,604 disclosing methyl hydroxamate derivatives of fenamic acid;
U.S. Pat. No. 3,413,313 disclosing ketoxime derivatives of fenamic acids;
EP Application No. 81103066.7 disclosing N-aminomethyl-N-acyl hydroxylamine prodrugs of hydroxamic acid derivatives including fenamates;
British 2212153A disclosing C(O)N(OR2)R1 derivatives of pyridyl-substituted phenyl containing groups including fenamate moieties.
These references differ from the present invention by at least the lack of a teaching to the present thiadiazole or oxadiazole derivative group.
Heteroaryl amino or aminoalkyl substituted phenyl hydroxamic acid derivatives are also known as 5-lipoxygenase inhibitors or antiinflammatory agents 15 as shown by the following references, for example:
WO 9001929A discloses among its substituents a furyl, thienyl, thienyl-1,1-dioxide, pyrrolyl, pyridyl, benzofuranyl, benzothienyl, benzothienyl-1,1 dioxide, indolyl, attached through an alkylamino to phenyl hydroxamic acid derivatives; (This appears to be an application related to EP 196184)
NL 8602610A discloses 5 benzoyl N hydroxy-2-thiophene acetamides with suggested substituents on the benzoyl including thienyl, furyl, tetrahydrofuryl, or pyridyl;
EP Application No. 196674 discloses various rings in a hydroxamate derivative including heterocycles.
These references teach compounds which each differ from the present invention by at least the lack of a fenamate ring system.
Heterocycle substituted fenamate derivatives are also known having one or both of the activity of the present invention, i.e., 5-lipoxygenase and cyclooxygenase inhibition. References showing this class of compounds include the following:
U.S. application Ser. No. 07/769,562 shows a thia- or oxadiazole analog of a fenamic acid.
U.S. Pat. No. 4,962,119 shows a triazolyl analog of fenamic acid.
U.S. application Ser. No. 697,822 shows thiazolidinone, oxazolidinone, and imidazolidinone derivatives of fenamates
These references teach compounds which each differ from the present invention by at least the lack of a substituted hydroxamate side chain